Immobilization of Molecules

The anchoring of molecules to a resin can usually be realized by two different strategies [8]. Direct loading is clearly the most straightforward technique for setting up solid-phase organic synthesis. A molecule with a reactive or potentially reactive functional group is coupled directly to the preformed linker. This strategy is useful if the linker and the building block can be coupled efficiently. Coupling rates >90% are essential at this point. Successful examples are, for instance, the formation of amide bonds, reductive amination reactions, alkylation reactions (including Mitsunobu reactions), and olefin metathesis. Because building blocks can be used without an additional purification step, this method is especially suitable for anchoring libraries of starting materials and/or automated synthesis attachment of molecules to a particular resin is highly dependent on the nature of the linker. Whereas simple and rapid mixing of reagents is sometimes sufficient to drive the attachment to completion, occasionally tedious monitoring is necessary. Sometimes attachment proceeds under similar conditions to those of detachment, for example formation of ketals, for which excess reagents are required to drive the reaction to completion.

In a second general method for attachment, the building block can be coupled to give the preformed linker in solution. The thus formed fragment, which is called the ''handle'' (see, for example, Ref. [11]; Figure 6.1.3), can then be activated for attachment on to the resin using the coupling strategies outlined above. Although this method requires an additional step in solution, the purity of the building block can be enhanced. This handle approach can be particularly favorable when the activated linker tends to decompose (for example silyl chlorides) or can be formed only in moderate yields and purities. In automated synthesis, however, the required solution-phase step is clearly a drawback.

452 I 6.1 Linkers for Solid-phase Synthesis FmocNH OMe

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